Note: Descriptions are shown in the official language in which they were submitted.
t3
PROLONGED-ACTION MULTIPLE-LAYER TABLETS
Field of the Invention:
The present invention relates to a prolonged-action
multiple-layer tablet having an increased rate of dissolution
of the active ingredient from a given point of time onward.
Background of the Invention:
Various methods have been proposed for preparing drugs
that are capable of maintaining the concentration of the
effective ingredient in blood for an extended period of time.
In particular, active efforts have been made to prepare orally
administered drugs that let the active ingredient be dissolved
in a given quantity in digestive tracts. It is possible by
the state-of-the-art technology to cause the drug substance
to be dissolved at a constant rate, but its absorption rate
is decreased as it moves toward the lower part of digestive
tracts, so with conventional long lasting drugs for oral
administration, there is high possibility that the concentration
of the active ingredient in blood is decreased as they move
along the digestive tract although -they have a constant
dissolution rate.
~0 As a result of various studies to solve this problem,
the present inventors have found the following: 1) if part
of a tablet is covered with an inert base havin~ substantially
the same disintegration rate, the dissolution of the drug
substance is prevented for a certain period after oral
administration, and when the tablet reaches a site in the
digestive tract where the rate of absorption of the drug
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substance is decreased, the disintegration of the inert
base is completed so as to increase the area of the
tablet from which the drug substance is released, hence
the amount of the substance to be absorbed by the di-
gestive tract; 2) the base for making such multiple-
layer tablet is preferably a mixture of a water-insol-
uble wax that is solid at ordinary temperatures, a dis-
integrator and a binder; and 3) the rate of disinteg-
ration of the base can be controlled over an extended
period by finely micronizing the water-insoluble wax
to an average particle size of 10 ~m or less, prefer-
ably 5 ~m or less, with a jet mill or other suitable
means.
Summary of the Invention:
The present invention has been accomplished on
the basis of these findings and relates to a prolonged-
action multip]e-layer tablet having an increased rate of
dissolution of the active ingredient from a given point
of time onward comprising layer A made of an intimate
mixture of a water-insoluble wax that has an average
particle size of 10 ~m or less and which is solid at
ordinary temperatures, a disintegrator and a binder, and
layer B made of an intimate mixture of a water-insoluble
wax that has an average particle size of 10 ~m or less
and which is solid at ordinary temperatures, a dis- `
integrator, a binder and the active ingredient.
The invention is explained by reference to the
accompanying drawings in which:
Figure 1 shows graphically the dissolution rate
with time of a tablet of the invention in comparison
with a matrix type tablet,
Figure 2 shows graphically the average concent-
ration of active ingredient in plasma with time, for the
tablet of Figure 1 in comparison with a matrix type
tablet,
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Figure 3 shows graphically the dis.solution rate
with time of another tablet of the invention,
Figure 4 shows graphically the average concent-
ration of active ingredient (acetyl salicylic acid) in
plasma with time9 for the tablet of Figure 3,
Figure 5 shows graphically the dissolution
rate with time of another tablet of the invention in
comparison with other tablets, and
Figure 6 shows graphically the average con-
centration of metabolite 1-(6-carboxylhexyl)-4-(o-
methoxyphenyl)piperazine in plasma with time for the
tablets of Figure 5.
Detailed Description of the Invention:
Examples of the water-insoluble wax that is
solid at ordinary temperatures include hydrogenated
castor oil, hydrogenated soybean oil, carnauba wax,
paraffin, palmitic acid, stearic acid, bees wax,
stearyl alcohol and octadecyl
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alcohol. Examples of the disinte~rator include low-substituted
hydroxypropyl cellulose, carboxymethyl cellulose, calcium
carboxymethyl cellulose, sodium carboxymethyl cellulose, corn
starch, sodium starch glycolate, and hydroxypropyl starch.
The disintegrator is used in an amount of from 0.5 to 40% (w/w),
preferably from 1 to 20% (w/w). Any compound can be used as
the binder if it dissolves or is digested in the digestive
tract, and illustrative examples include hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose
phthalate, gelatin, ~-starch, polyvinyl pyrrolidone and
polyethylene glycol. The binder is used in an amount of from
0.1 to 30~ (w/w), preferably from 0.5 to 15% (w/w). The
binder is used as a solution in a suitable solvent. Needless
to say, a suitable coloring agent, lubricant, flavoring agent
-and diluent may be incorporated in the tablet of the present
invention as required.
Example 1
Hydrogenated castor oil (I.ubriwax 101 from Freund Inc.
Co., Ltd.) was micronized into fine particles of a mean size
of 1.5 ~m (as measured by the centrifugal sedimentation method)
with a micro jet mill (Model FS-~ of Seishin Enterprise Co.,
~td., Japan). Ninety grams of the particles was intimately
mixed with 8 g of low-substituted hydroxypropyl cellulose
(L-HPC-LH-31 from Shinetsu Chemical Co., Ltd., Japan) in a
mortar. The mixture was kneaded well with 20 g of a 10% (w/w)
aqueous solution of hydroxypropyl cellulose (HPC-L from Nihon
Soda Co., Ltd., Japan) and 43 g of pure water. The blend was
sifted through a 20 mesh sieve into a ~ranulation which was
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dried in a tray drier at 50C for 5 hours. Then, the granula-
tion was classified through a 14 mesh sieve and the product
was referred to as granulation (a).
Granulation (a) (42.5 g) and 7.5 g of a nitrate ester
of N-(2-hydroxyethyl)nicotinic acid amide that had been screened
through a 35 mesh sieve were intimately mixed in a polyethylene
bag to form granules which were referred to as granulation (b).
Lactose ~5.9 g), 3 g of crystalline cellulose, 0.1 g
of calcium stearate and l g of a nitrate ester of N-(2-
hydroxyethyl)nicotinic acid amide that had been screened througha 35 mesh sieve were intimately mixed in a polyethylene bag
to form a powder which was referred to as powder (c).
A single-punch machine with a lO mm~ die and a flat-
face punch was used to make tablets. First, the die was
filled with 80 mg of granulation (a) whi~h was given a light
stroke of precompression. The die was further filled with
200 mg of granulation (b) which was also given a light stroke
of precompression. Then, the die was filled with 30 mg of
powder (c) which together with the first and second fills
was compacted under a total pressure of about l ton into a
tablet.
For comparison, matrix type tablets were prepared by
the conventional method using ethyl cellulose. Each tablet
(310 mg) contained 33 mg of a nitrate ester of N-(2-hydroxy-
ethyl)nicotinic acid amide.
The profile of dissolution of the two kinds of tablet
is shown in Figs. l and 2. Fig. l is the dissolution rate
vs. time curve for a solution having ~ pH of 6.8. Fig. 2 is
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the average concentration of the active ingregient in plasma
vs. time curve when the tablets were administered to 6 beagles.
Example 2
Carnauba wax was micronized into fine particles of
a mean size of 2.2 ~m (as measured by the centrifugal sedi-
mentation method) wlth a micro jet mill (Model FS-4 of Seishin
Enterprise Co.~ Ltd.). A hundred and forty grams of the
particles was intimately mixed with 6 g of calcium carboxy-
methyl cellulose (ECG-505 from Gotoku Yakuhin Kogyo, Japan)
and 50 g of acetyl salicylic acid in a mortar. The mixture
was ~neaded well with 100 g of a 4% solution of hydroxypropyl-
methyl cellulose (60SH-50 from Shinetsu Chemical Co., Ltd.)
in 50~ ethanol. The blend was granulated with a rotary
granulator having a 0.8 mm~ net. The granulation was dried
in a fluid-bed dryer at 60C for 20 minutes and classified
through a 14 mesh sieve. The resulting product was referred
to as granulation (a).
Stearic acid was micronized into fine particles of a
mean size of 2.9 ~m (as measured by the centrifugal sedimenta-
tion method) with a micro jet mill (Model ~S-4 of Seishin
Enterprise Co., Ltd.).~ Eighty-four grams of the particles
was intimately mixed with 4 g of carboxymethyl cellulose
(NS-300 from Gotoku Yakuhin Kogy~) and 10 g of mannitol in a
mortar. The mixture was kneaded well with 50 g of a 4%
solution o~ hydroxypropyl cellulose (HPC-M of Nihon Soda Co,,
Ltd.) in 50% ethanol. The blend was granulated with a rotary
granulator having a 0.8 mm~ net. The granulation was dried
with a fluid-bed dryer at 50C for 40 minutes, and classified
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through a 14 mesh sieve. The resulting product was referred
to as granu]ation (b).
A single punch machine with a 10 mm~ die and a flat-
face bevel-edge punch with a score line was used to make
tablets. First, the die was filled with 200 mg of granula-
tion (a) which was given a light stroke of precompression.
The die was then filled with 100 mg of granulation (b) which
together with the first fill was compacted under a total
pressure of about 1 ton into a tablet.
The profile of dissolution of the tablets so prepared
is shown in Figs. 3 and 4. Fig. 3 is the dissolution rate
vs. time curve for a solution having a pH of 6.8. Fig. 4 is
the average concentration of the active ingredient in plasma
vs. time curve when five tablets were administered to 4 beagles.
Example 3
Hydrogenated soybean oil tLubriwax 102H from Freund
Inc. Co., Ltd.) was micronized into fine particles of a mean
size of 3.1 ~m (as measured by the centrifugal sedimentation
method) with a micro jet mill (Model FS-4 of Seishin Enterprise
Co., Ltd.). Sixty-six grams of the particles was intimately
mixed with 12 g of low-substituted hydroxypropyl cellulose
(L-HPC~LH-31 from Shinetsu Chemical Co., Ltd.) and 10 g of
ethyl 7-[4-(2-methoxyphenyl)-1-piperazino]-heptanoate monofuma-
rate in a mortar. The blend was kneaded well with 40 g of
a 30~ tw/w) aqueous solution of hydroxypropyl cellulose
(HPC-SL of Nihon Soda Co., Ltd.). The blend was sifted
through a 20 mesh sieve into a granulation which was dried
in a tray drier at 50C for 5 hours. Then, the granulation
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was classified through a 14 mesh sieve and the product was
referred to as granulation (a).
Hydrogenated soybean oil (Lubriwax 102H from Freund
Inc. Co., Ltd.) was ~icronized into fine particles with a
micro jet mill (Model FS-4 of Seishin Enterprise Co., Ltd.),
and 76 g of the particles was intimately mixed with 12 g of
low-substituted hydroxypropyl cellulose (L-HPC-LH-31 from
Shinetsu Chemical Co., Ltd.) in a mortar. The blend was
kneaded well with 40 g of a 30~ ~w/w) aqueous solution of
hydroxypropyl cellulose (HPC-SL from Nihon Soda Co., Ltd.)
and 3 g of pure water. The blend was sifted through a 20 mesh
sieve into a granulation which was dried in a tray drier at
50C for 5 h'ours. Then~ the granulation was classified through
a 14 mesh sieve and the product was referred to as granulation (b).
A single-punch machine with a 10 mm~ die and a standard
13 R punch was used to make tablets. First, the die was
filled with 200 mg of granulation (a) which was given a light
stroke of precompression. The die was then filled with' 100
mg of granulation (b) which together with the first fill was
compacted under a total pressure of about 1 ton into a tablet~
For comparison, multiple-layer tablets were prepared
~y the same method except that the hydrogenated soybean oil
was not finely micronized and had a particle size of 20 to
80 ~m as measured under a microscope.
The profile of dissolution of the two kinds of tablet
is shown in Figs. 5 and 6. Fig. S is the dissolution rate vs.
time curve for a solution having a pH of 2.2. Fig. 6 depicts
a curve for time vs. average concentration of metabolite
1-(6-carboxylhexyl)-4-(o-methoxyphenyl)piperazine in plasma
when each tablet was administered to 6 beagles.
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